Crystalline acid of lipoxin A4 analogs and method of making

Abstract

This invention is directed to a crystalline acid of a lipoxin A 4 analog of Formula (II): wherein: R 1 is —O—, —S(O) t — (where t is 0, 1 or 2), or a straight or branched alkylene chain; and R 2 is aryl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from f alkyl, alkoxy, halo, haloalkyl and haloalkoxy); and wherein the compound of Formula (II) is a single stereoisomer or any mixture of stereoisomers. This crystalline acid is useful in treating disease-states characterized by inflammation, such as inflammatory and autoimmune disorders or pulmonary or respiratory tract inflammations in humans. Methods of preparing the crystalline acid are also described.

1 . A crystalline acid of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is —O—, —S(O) t — (where t is 0, 1 or 2), or a straight or branched alkylene chain; and 
 R 2  is aryl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy); 
 
       and wherein the compound of Formula (II) is a single stereoisomer or any mixture of stereoisomers. 
     
     
         2 . The crystalline acid according to  claim 1  wherein R 1  is —O— and R 2  is phenyl optionally substituted by one or more substituents selected from fluoro, chloro and iodo. 
     
     
         3 . The crystalline acid according to  claim 2  wherein R 1  is —O— and R 2  is 4-fluorophenyl, as a single stereoisomer or any mixture of stereoisomers. 
     
     
         4 . The crystalline acid according to  claim 3 , wherein the crystalline acid is: 
       2-((2S,3R,4E,6E,10E,1 2S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2R,3R,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2S,3S,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2R,3S,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2S,3R,4E,6E,10E,12R)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2R,3R,4E,6E,10E,12R)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2S,3S,4E,6E,10E,12R)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; or 
       2-((2R,3S,4E,6E,10E,12R)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid. 
     
     
         5 . The crystalline acid according to  claim 3 , wherein the crystalline acid is 2-((2S,3R,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The crystalline acid according to  claim 1  wherein the crystalline acid is in anhydrous form. 
     
     
         7 . The crystalline acid according to  claim 1  wherein the crystalline acid is in the form of a hydrate 
     
     
         8 . The crystalline acid according to  claim 1  wherein the crystalline acid is in the form of a mixture of anhydrate and hydrate. 
     
     
         9 . The crystalline acid according to  claim 5 , wherein the crystalline acid is 2-((2S,3R,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid 
       
         
           
           
               
               
           
         
       
       in an anhydrous form which exhibits characteristic peaks at d=20.48 Å and at d=4.34. 
     
     
         10 . The crystalline acid according to  claim 5 , wherein the crystalline acid is 2-((2S,3R,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid 
       
         
           
           
               
               
           
         
       
       and forms a hydrate which exhibits characteristic peaks at d=9.8 Å and at d=4.6 Å. 
     
     
         11 . A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a crystalline acid of  claim 1 . 
     
     
         12 . A method of treating a disease-state characterized by inflammation in a mammal, the method comprising administering to the mammal in need thereof a therapeutically effective amount of a crystalline acid of  claim 1 . 
     
     
         13 . The method according to  claim 12  wherein the disease-state is an inflammatory or autoimmune disorder. 
     
     
         14 . The method according to  claim 12  wherein the disease-state is a pulmonary or respiratory tract inflammatory disorder. 
     
     
         15 . A method of synthesizing a crystalline acid of Formula (II): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is —O—, —S(O) t — (where t is 0, 1 or 2), or a straight or branched alkylene chain; and 
 R 2  is aryl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy); 
 
         as a single stereoisomer or any mixture of stereoisomers; 
       
       the method comprising:
 1) mixing an alkali hydroxide base, in a suitable solvent, together with an ester of Formula (IV), in a suitable solvent: 
 
       
         
           
           
               
               
           
         
         
           wherein R 1  and R 2  are as defined above, and R is alkyl or aryl; 
         
         2) acidifying the resulting mixture by treatment with an acid; 
         3) isolating the resulting crystals from the resulting suspension; 
         4) optionally washing the isolated crystals with a suitable solvent; and 
         5) drying the isolated crystals, to give the final product crystalline acid. 
       
     
     
         16 . The method according to  claim 15  wherein the suitable solvent for the alkali hydroxide base comprises an organic solvent and water. 
     
     
         17 . The method according to  claim 15  which comprises the additional step, prior to acidifying the mixture, of adding water in an amount sufficient to effect suitable crystallization of the product upon acidification 
     
     
         18 . The method according to  claim 15  wherein R 1  is —O— and R 2  is phenyl optionally substituted by one or more substituents selected from fluoro, chloro and iodo. 
     
     
         19 . The method according to  claim 15  wherein the final product crystalline acid is: 
       2-((2S,3R,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2R,3R,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2S,3S,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2R,3S,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2S,3R,4E,6E,10E,12R)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       2-((2R,3R,4E,6E,10E,12R)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; 
       potassium 2-((2S,3S,4E,6E,10E,12R)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid; or 
       potassium 2-((2R,3S,4E,6E,10E,12R)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid. 
     
     
         20 . The method according to  claim 15 , wherein the final product crystalline acid is 2-((2S,3R,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid: